Keeping Cancer in Check
Harnessing the power of the immune system to fight cancer
The use of immunotherapy for treating cancer is receiving a lot of attention of late. The American Cancer Society, US National Cancer Institute andAmerican Association for Cancer Research are among the organizations that are talking about how promising this new revolution in cancer therapy appears to be. The US Food and Drug Administration recently approved Merck's immune-based therapy called Keytruda for advanced melanoma. It is definitely a hot topic right now.
Surprisingly, the idea of using the immune system to fight cancer is not a new one. Fifty years ago, Lewis Thomas and Nobel laureate Frank Macfarlane Burnet suggested that T-cells were the pivotal sentinel in the immune system's response to cancer.1 At the time, such theories were considered highly controversial. Fast forward to 2014 and we now have a number of observations that support this notion that immunosurveillance plays a critical role in identifying and elimination malignant cancer cells:2
- Primary immunodeficiency in mice and humans is associated with increased cancer risk
- Organ transplant recipients who are treated with immunosuppressive drugs are more prone to cancer development
- AIDS leads to elevated risk of cancer
- Immune cell infiltrate found in tumors is measured and used as a prognostic factor for patient survival
- Cancer cells harbor mutations in protein-coding genes that are specifically recognized by the adaptive immune system
- Cancer cells selectively accumulate mutations to evade immune destruction ("immunoediting")
- Lymphocytes bearing the NKG2D receptor are able to recognize and eliminate stressed premalignant cells
- A promising strategy to treat cancer consists on potentiating the naturally occurring immune response of the patient, through blockade of immune checkpoint molecules
The actual genesis of cancer immunotherapy goes back even further than the concept of immunosurveillance. In the late 19th century, Dr. William Coley, also known as the Father of Immunology, noticed that the tumors of some patients disappeared following high fevers from an unrelated infection.
On the basis of these observations, Coley treated his first patient with streptococcal organisms and noted a shrinkage of a malignant tumor.3 Over the next 40 years he injected more than 1,000 cancer patients with bacteria or bacterial products, reporting excellent results. Most of the treated patients had inoperable sarcomas, with the bacterial toxin achieving a cure rate of over 10%.4
The tools with which cancer immunotherapy has been studied have an interesting history as well. In the mid-1950s, syngeneic models were used, in which mouse cancer cells were implanted subcutaneously in mice. If human cancer cells were implanted into mice the cells would be rejected as foreign by the immune system. In the 1960s, "nude mice" with a compromised immune system were developed and in the 1970s scientists figured out how human cancer cells could be implanted into those mice without being rejected. These cancer models were called xenograft models. However, by the 1980s, researchers were turning back to the syngeneic models again, due to a need to study tumor growth with an intact immune system.
Checkmate on Cancer
Today there are a number of different ways in which the immune system is manipulated to keep cancer in check. One can introduce tumor antigens into the body either by injecting vaccines containing the antigen or injecting dendritic cells already loaded with tumor antigens to trigger an immune response to the tumor cells. Another way in which the immune system can be exploited to fight cancer is to enhance the expansion of activated T-cells, or even manipulate the patient's own T-cells and reintroducing them, primed and ready to find and eliminate the invading cancer cells.
It's no secret that most cancer treatments involve a nasty cocktail of cytotoxic agents that lack specificity for tumor cells and exhibit cumulative dose-dependent toxicity that limit their utility. When treatment is withdrawn due to toxicity, the tumors continue growing with renewed vigor. Moreover, tumor cells often develop resistance to the cytotoxic agents in an effort to circumvent any attempt to stop the tumor growth. In contrast, cancer immunotherapies are designed to bolster the patient's own immune system to fight the cancer and generally don't harbor the same toxicity. As an added dividend, the T-cells and B-cells that comprise the adaptive arm of our immune system have long "memories" so if the cancer returns they should, theoretically, be able to mount a strong secondary response. This is what is referred to as durable therapeutic response.
Still, the regulation of the immune system is very complex and is constantly in delicate balance. When the body's immune system goes out of balance, it attacks itself in the form of an autoimmune response, recognizing a native protein as something foreign, as is the case with rheumatoid arthritis or lupus.
There are a number of very complex interconnected systems that regulate the immune response to a foreign substance. One such system involves so-called checkpoint molecules. About two decades ago, Texas scientist James Allison found a protein, cytotoxic T lymphocyte antigen-4 (CTLA-4), on T cells that acted as a kind of brake by shutting down the T cells and preventing the immune system from going rogue. CTLA-4 was a checkpoint in the immune response. Allison theorized that if you could temporarily let up on these brakes by inhibiting the CTLA-4 protein, you might be able to provide a more robust immune response.
This led to the development and eventual approval of the monoclonal antibody Yervoy last year for advanced melanoma, the first of a rapidly growing list of CTLA-4 inhibitors in the pipeline. To give you an idea of how hot these agents are, about 100 clinical trials for CTLA-4 inhibitors are ongoing right now. And these aren't the only checkpoint proteins being targeted. Researchers have developed drugs that inhibit programmed cell death 1 (PD1)—pembrolizumab (Keytruda) being one example—and LAG-3. Other checkpoint proteins can potentially be exploited as well.5 What's more is that scientists are finding that using two or more checkpoint inhibitors in combination result in a synergistic effect that is more than just additive.6
At Charles River we have been working to validate and characterize even more syngeneic models with various combinations of CTLA-4 and PD-1 checkpoint inhibitors to bolster the already extensive set of tools we have to assess new and exciting immunomodulators for the treatment of cancer. It is truly humbling to play a part in the discovery and development of new cancer therapies that profoundly impact patients and their families and to think that some of these new therapies may actually lead to a cure for cancer.
- Burnet, F.M. Prog Exp Tumor Res 1970 13:1–27.
- Corthay, A. Frontiers in Immunology, doi: 10.3389/fimmu. 2014.00197 May 12
- McCarthy, E.F. Iowa Orthop J 2006 26:154–158.
- Wiemann, B. and Starnes, C.O. Pharmacol Ther. 1994 64:529–564.
- Pardoll, D.M. Nature Reviews Cancer 2012 12:252-264.
- Lu, L. et al. J Transl Med 2014 12:36-47.